Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14ARF and retinoic acid receptor β signaling

Christina Dahl, Claus Christensen, Goran Jonsson, Anders Blomkild Lorentzen, Mette louise Skjøds, Åke Borg, Graham Pawelec, Per Guldberg

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    Resumé

    Melanoma genomes contain thousands of alterations, including mutations, copy number alterations, structural aberrations and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, we generated a profile of genetic and epigenetic drivers in 110 human melanoma cell lines and searched for non-random distribution patterns. We found statistically significant mutual exclusivity among components of each of the p16INK4A-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT pathways. In addition, we found an inverse correlation between promoter hypermethylation of RARB (encoding retinoic acid receptor β (RARβ)) and CDKN2A alterations affecting p14ARF (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. We show that all-trans retinoic acid (ATRA) can increase the expression of p14ARF in primary human melanocytes, and that the steady-state levels of p14ARF in these cells are regulated via RARβ. Furthermore, we show that the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF axis, independent of p16INK4A and p53 status. These data identify a previously unrecognized crosstalk between RARβ and p14ARF with possible implications for melanoma treatment, and highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways.
    OriginalsprogEngelsk
    TidsskriftMolecular Cancer Research
    Vol/bind11
    Udgave nummer10
    Sider (fra-til)1166-1178
    Antal sider13
    ISSN1541-7786
    DOI
    StatusUdgivet - 12 jul. 2013

    Citer dette

    Dahl, Christina ; Christensen, Claus ; Jonsson, Goran ; Lorentzen, Anders Blomkild ; Skjøds, Mette louise ; Borg, Åke ; Pawelec, Graham ; Guldberg, Per. / Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14ARF and retinoic acid receptor β signaling. I: Molecular Cancer Research. 2013 ; Bind 11, Nr. 10. s. 1166-1178.
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    title = "Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14ARF and retinoic acid receptor β signaling",
    abstract = "Melanoma genomes contain thousands of alterations, including mutations, copy number alterations, structural aberrations and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing {"}drivers{"} that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, we generated a profile of genetic and epigenetic drivers in 110 human melanoma cell lines and searched for non-random distribution patterns. We found statistically significant mutual exclusivity among components of each of the p16INK4A-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT pathways. In addition, we found an inverse correlation between promoter hypermethylation of RARB (encoding retinoic acid receptor β (RARβ)) and CDKN2A alterations affecting p14ARF (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. We show that all-trans retinoic acid (ATRA) can increase the expression of p14ARF in primary human melanocytes, and that the steady-state levels of p14ARF in these cells are regulated via RARβ. Furthermore, we show that the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF axis, independent of p16INK4A and p53 status. These data identify a previously unrecognized crosstalk between RARβ and p14ARF with possible implications for melanoma treatment, and highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways.",
    author = "Christina Dahl and Claus Christensen and Goran Jonsson and Lorentzen, {Anders Blomkild} and Skj{\o}ds, {Mette louise} and {\AA}ke Borg and Graham Pawelec and Per Guldberg",
    year = "2013",
    month = "7",
    day = "12",
    doi = "10.1158/1541-7786.MCR-13-0006",
    language = "English",
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    pages = "1166--1178",
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    Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14ARF and retinoic acid receptor β signaling. / Dahl, Christina; Christensen, Claus; Jonsson, Goran; Lorentzen, Anders Blomkild; Skjøds, Mette louise; Borg, Åke ; Pawelec, Graham; Guldberg, Per.

    I: Molecular Cancer Research, Bind 11, Nr. 10, 12.07.2013, s. 1166-1178.

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

    TY - JOUR

    T1 - Mutual exclusivity analysis of genetic and epigenetic drivers in melanoma identifies a link between p14ARF and retinoic acid receptor β signaling

    AU - Dahl, Christina

    AU - Christensen, Claus

    AU - Jonsson, Goran

    AU - Lorentzen, Anders Blomkild

    AU - Skjøds, Mette louise

    AU - Borg, Åke

    AU - Pawelec, Graham

    AU - Guldberg, Per

    PY - 2013/7/12

    Y1 - 2013/7/12

    N2 - Melanoma genomes contain thousands of alterations, including mutations, copy number alterations, structural aberrations and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, we generated a profile of genetic and epigenetic drivers in 110 human melanoma cell lines and searched for non-random distribution patterns. We found statistically significant mutual exclusivity among components of each of the p16INK4A-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT pathways. In addition, we found an inverse correlation between promoter hypermethylation of RARB (encoding retinoic acid receptor β (RARβ)) and CDKN2A alterations affecting p14ARF (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. We show that all-trans retinoic acid (ATRA) can increase the expression of p14ARF in primary human melanocytes, and that the steady-state levels of p14ARF in these cells are regulated via RARβ. Furthermore, we show that the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF axis, independent of p16INK4A and p53 status. These data identify a previously unrecognized crosstalk between RARβ and p14ARF with possible implications for melanoma treatment, and highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways.

    AB - Melanoma genomes contain thousands of alterations, including mutations, copy number alterations, structural aberrations and methylation changes. The bulk of this variation is stochastic and functionally neutral, with only a small minority representing "drivers" that contribute to the genesis and maintenance of tumors. Drivers are often directly or inversely correlated across tumors, reflecting the molecular and regulatory signaling pathways in which they operate. Here, we generated a profile of genetic and epigenetic drivers in 110 human melanoma cell lines and searched for non-random distribution patterns. We found statistically significant mutual exclusivity among components of each of the p16INK4A-CDK4-RB, RAS-RAF-MEK-ERK and PI3K-AKT pathways. In addition, we found an inverse correlation between promoter hypermethylation of RARB (encoding retinoic acid receptor β (RARβ)) and CDKN2A alterations affecting p14ARF (P < 0.0001), suggesting a functional link between RARβ signaling and the melanoma-suppressive activities of p14ARF. We show that all-trans retinoic acid (ATRA) can increase the expression of p14ARF in primary human melanocytes, and that the steady-state levels of p14ARF in these cells are regulated via RARβ. Furthermore, we show that the ability of ATRA to induce senescence is reduced in p14ARF-depleted melanocytes, and we provide proof-of-concept that ATRA can induce irreversible growth arrest in melanoma cells with an intact RARβ-p14ARF axis, independent of p16INK4A and p53 status. These data identify a previously unrecognized crosstalk between RARβ and p14ARF with possible implications for melanoma treatment, and highlight the power of mutual exclusivity analysis of cancer drivers to unravel molecular pathways.

    U2 - 10.1158/1541-7786.MCR-13-0006

    DO - 10.1158/1541-7786.MCR-13-0006

    M3 - Journal article

    VL - 11

    SP - 1166

    EP - 1178

    JO - Molecular Cancer Research

    JF - Molecular Cancer Research

    SN - 1541-7786

    IS - 10

    ER -